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Pituitary Resistance to Thyroid Hormone Syndrome Is Associated with T₃ Receptor Mutants that Selectively Impair ß2 Isoform Function

Section of Microbiology, Division of Biological Sciences, University of California at Davis, Davis, California 95616

Address all correspondence and requests for reprints to: Martin L. Privalsky, Section of Microbiology, One Shields Avenue, University of California at Davis, Davis, California 95616. E-mail: mlprivalsky{at}ucdavis.edu.

Resistance to thyroid hormone (RTH) syndrome is an inherited inability to respond appropriately to T₃ hormone. In generalized RTH, the T₃ response of both the pituitary and periphery is disrupted. In pituitary (or central) RTH, the ability of the pituitary to sense (and down-regulate) elevated T₃ is selectively impaired, whereas the periphery remains relatively T₃ responsive, resulting in peripheral thyrotoxicity. Both forms of disease are linked to mutations in thyroid hormone receptor (TR)-ß. TRß is expressed by alternate mRNA splicing as two isoforms: TRß2, found primarily in the pituitary/hypothalamus, and TRß1, expressed broadly in many tissues. We report here that the wild-type TRß2 isoform displays an enhanced T₃ response relative to the TRß1 isoform. Mutations associated with generalized RTH (P453S, G345S) impair both TRß2 and TRß1 function proportionally, whereas mutations associated with pituitary-specific RTH (R338L, R338W, R429Q) disproportionately disrupt TRß2 function. We propose that in the normal organism, and in generalized RTH, TRß2 in the pituitary can sense rising T₃ levels in advance of TRß1 in the periphery, preventing thyrotoxicity. In contrast, the TRß mutations associated with pituitary RTH disproportionately disrupt the pituitary’s ability to sense and suppress elevated T₃ levels in advance of the periphery, producing symptoms of thyrotoxicity.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ

Coregulators:   SRC-1  |  GRIP1  |  NCOR  |  SMRT

Ligands:   Thyroid hormone

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